There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. RNA-protein complexes represent an important and under utilized drug target. In HIV, the Tat-TAR and Rev-RRE RNA- protein complexes carry out essential roles in RNA transcription and nuclear export respectively. Disruption of these RNA-protein complexes can inhibit viral replication, thus this strategy holds great promise for antiviral drug discovery. Advanced Genetic Systems (AGS) and UCSF have jointly developed a cell- based drug-screening platform to target RNA and RNA-protein complexes. The screening platform was rigorously evaluated with control inhibitors and a pilot screen of 4500 small molecule compounds targeting Rev-RRE. From this screen, we identified novel compounds that specifically target Rev, exhibit low toxicity, display favorable pharmacokinetic properties, and inhibit HIV replication at sub-micromolar IC50s. This result has given us great confidence that we have developed a high-quality, robust screening platform capable of identifying inhibitors of viral RNA-protein targets. We now wish to use our screening platform to carry out expanded screens targeting HIV Rev- RRE and Tat-TAR. We will screen a small molecule diversity library to identify new molecular entities that could form the basis of new classes of anti-HIV therapeutics. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: There is significant need to develop new classes of antiviral drugs to combat emerging viral diseases and resistance to older drugs. RNA-protein complexes represent an important and under utilized viral drug target. Disruption of an RNA-protein complex can inhibit viral replication, thus this strategy holds great promise for antiviral drug discovery. [unreadable] [unreadable] [unreadable]